Coronary Artery Disease (CAD) affects 1.5 million people in the USA annually. About 10% of these patients die within the first year and about 900,000 suffer from acute myocardial infarction. During CAD, formation of plaques under the endothelial tissue narrows the lumen of the coronary artery and increases its resistance to blood flow, thereby reducing the O.sub.2 supply. Injury to the myocardium (i.e., the middle and thickest layer of the heart wall, composed of cardiac muscle) fed by the coronary artery begins to become irreversible within 0.5-1.5 hours and is complete after 6-12 hours, resulting in a condition called acute myocardial infarction (AMI) or simply myocardial infarction (MI).
Myocardial infarction is a condition of irreversible necrosis of heart muscle that results from prolonged ischemia. Damaged regions of the myocardium are infiltrated with noncontracting scavenger cells and ultimately are replaced with scar tissue. This fibrous scar does not significantly contribute to the contraction of the heart and can, in fact, create electrical abnormalities.
Those who survive AMI have an 4-6 times higher risk of developing heart failure. Current and proposed treatments for those who survive AMI focus on pharmacological approaches and surgical intervention. For example, angioplasty, with and without stents, is a well known technique for reducing stenosis. Most treatments are designed to achieve reperfusion and minimize ventricular damage. However, none of the current or proposed therapies address myocardial necrosis (i.e., degradation and death of the cells of the heart muscle). Because cardiac cells do not divide to repopulate the damaged region, this region will fill with connective tissue produced by invading fibroblasts. Fibroblasts produce extracellular matrix components of which collagen is the most abundant. Neither the fibroblasts themselves nor the connective tissue they form are contractile. Thus, molecular and cellular cardiomyoplasty research has evolved to directly address myocardial necrosis.
Cellular cardiomyoplasty involves transplanting cells, rather than organs, into the damaged myocardium with the goal of restoring its contractile function. Research in the area of cellular cardiomyoplasty is reviewed in Cellular Cardiomyoplasty: Myocardial Repair with Cell Implantation, ed. Kao and Chiu, Landes Bioscience (1997), particularly Chapters 5 and 8. For example, Koh et al., J. Clinical Invest., 96, 2034-2042 (1995), grafted cells from AT-1 cardiac tumor cell line to canines, but found uncontrolled growth. Robinson et al., Cell Transplantation, 5, 77-91 (1996),grafted cells from C.sub.2 C.sub.12 skeletal muscle cell line to mouse ventricles. Although these approaches produced intriguing research studies, cells from established cell lines are typically rejected from the human recipient. Li et al., Annals of Thoracic Surqerv, 62, 654-661 (1996), delivered fetal cardiomyocytes to adult mouse hearts. They found improved systolic pressures and noticed that the presence of these cells prevented remodeling after the infarction. Although their results showed the efficacy of transplanted cell technology, this approach would not likely be effective in clinical medicine since the syngeneic fetal cardiac tissue will not be available for human patients. Chiu et al., Ann. Thorac. Surg., 60,1 2-18 (1995) performed direct injection of cultured skeletal myoblasts to canine ventricles and found that well developed muscle tissue could be seen. This method, however, is highly invasive, which compromises its feasibility on human MI patients.
Molecular cardiomyoplasty has developed because fibroblasts can be genetically manipulated. That is, because fibroblasts, which are not terminally differentiated, arise from the same embryonic cell type as skeletal muscle, their phenotype can be modified, and possibly converted into skeletal muscle satellite cells. This can be done by turning on members of a gene family (myogenic determination genes or "MDGS") specific for skeletal muscle. A genetically engineered adeno-virus carrying the myogenin gene can be delivered to the MI zone by direct injection. The virus penetrates the cell membrane and uses the cell's own machinery to produce the myogenin protein. Introduction of the myogenin protein into a cell turns on the expression of the myogenin gene, which is a skeletal muscle gene, and which, in turn, switches on the other members of the MDGS and can transform the fibroblast into a skeletal myoblast. To achieve this gene cascade in a fibroblast, replication deficient adenovirus carrying the myogenin gene can be used to deliver the exogenous gene into the host cells. Once the virus infects the fibroblast, the myogenin protein produced from the viral genes turns on the endogenous genes, starting the cascade effect, and converting the fibroblast into a myoblast. Without a nuclear envelope, the virus gets degraded, but the cell's own genes maintain the cell's phenotype as a skeletal muscle cell.
This concept has been well-developed in vitro. For example, Tam et al., J. Thoracic and Cardiovascular Surgery, 918-924 (1995), used MyoD expressing retrovirus in vitro for fibroblast to myoblast conversion. However, its viability has not been demonstrated in vivo. For example, Klug et al., J. Amer. Physiol. Society, 1913-1921 (1995), used SV40 in vivo and succeeded in replicating the nucleus and DNA, but not the cardiomyocytes themselves. Also, Leor et al., J. Molecular and Cellular Cardiology, 28, 2057-2067 (1996), reported the in situ generation of new contractile tissue using gene delivery techniques.
Thus, there is a need for an effective system and the method for less invasive delivery of a source of repopulating agents, such as cells or vectors, to the location of the infarct zone of the myocardium.
Many of the following lists of patents and nonpatent documents disclose information related to molecular and cellular cardiomyoplasty techniques. Others are directed to background information on myocardial infarction, for example.
TABLE 1a ______________________________________ Patents Patent No. Inventor(s) ______________________________________ 4,379,459 Stein 4,411,268 Cox 4,476,868 Thompson 4,556,063 Thompson et al. 4,821,723 Baker et al. 5,030,204 Badger et al. 5,060,660 Gambale et al. 5,069,680 Grandjean 5,104,393 Isner et al. 5,131,388 Pless 5,144,949 Olson 5,158,078 Bennett et al. 5,205,810 Guiraudon et al. 5,207,218 Carpentier et al. 5,312,453 Shelton et al. 5,314,430 Bardy 5,354,316 Keimel 5,510,077 (Dinh et al.) 5,545,186 Olson et al. 5,658,237 Francishelli 5,697,884 Francishelli et al. ______________________________________
TABLE 1b ______________________________________ Foreign Patent Documents Document No. Applicant Publication Date ______________________________________ WO 93/04724 Rissman et al. 03/15/93 WO 94/11506 Leiden et al. 05/26/94 WO 95/05781 Mulier et al. 03/02/95 WO 97/09088 Elsberry et al. 03/13/97 ______________________________________
TABLE 1c ______________________________________ Nonpatent Documents ______________________________________ Acsadi et al, The New Biol., 3, 71-81 (1991). Barr et al., Gene Ther., 1, 51-58 (1994). Cellular Cardiomyoplasty: Myocardial Repair with Cell Implantation, ed. Kao and Chiu, Landes Bioscience (1997) Chiu et al., "Cellular Cardiomyoplasty: Myocardiol Regeneration With Satellite Cell Implantation", Ann. Thorac. Surg., 60, 12-18 (1995). Fletcher et al., "Acute Myocardiol Infarction", Pathophysiology of Heart Disease, French et al., Circulation, 90, 2414-2424 (1994). Gal et al., Lab. Invest., 68, 18-25 (1993). Innis et al. Eds. PCR Strategies, 1995, Academic Press, New York, New York. Johns, J. Clin. Invest., 96, 1152-1158 (1995). Klug et al., J. Amer. Physiol. Society, 1913-1921 (1995). Koh et al., J. Clinical Invest., 96, 2034-2042 (1995). Leor et al., J. Molecular and Cellular Cardiology, 28, 2057-2067 (1996) Li et al., Annals of Thorasic Surgery, 60, 654-661 (1996). Mesri et al., "Expression of Vascular Endothelial Growth Factor From a Defective Herpes Simplex Virus Type 1 Amplicon Vector Induces Angiogenesis in Mice", Department of Medicine, Division of Endocrinology, Diabetes Research Center, Bronx, New York (Received 08/19/94, accepted 11/03/94), 1995, American Heart Association. Molecular Cloning: A Laboratory Manual, 1989 Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York. Murry et al., J. Clin. Invest., 98, 2209-2217 (1196) Olson, "Remington's Pharmaceutical Sciences", a standard reference text in this field. Parmacek et al, J. Biol. Chem., 265, 15970-15976 (1990). Parmacek et al., Mol. Cell. Biol., 12, 1967-1976 (1992). Robinson et al., Cell Transplantation, 5, 77-91 (1996). Robinson et al., "Implantation of Skeletal Myoblast-Derived Cells", Cellular Cardiomyoplasty: Myocardiol Repair with Cell Implantation, eds. R. Kao and R. C-J. Chiu, Landes Bioscience (1997). Sambrook et al., Molecular Cloning: A Laboratory Manual, 1989, Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York. Symes, "Therapeutic Angiogenesis for Coronary Artery and Peripheral Vascular Disease", LAD, July 1997 (XIX Annual Meeting of ISHR- American Section. Tam et al., J. Thorasic and Cardiovascular Surgery, 918-924 (1995). Taylor et al., "Delivery of Primary Autologous Skeletal Myoblasts into Rabbit Hear by Coronary Infusion: A Potential Approach to Myocardial Repair", Proceedings of the Association of American Physicians, 109, 245-253 (1997). von Recumin et al., Biomaterials, 12, 385-389, "Texturing of Polymer Surfaces at the Cellular Level" (1991). von Recumin et al., Biomaterials, 13, 1059-1069, "Macrophage Response to Microtextured Silicone" (1992). von Recumin et al., Journal of Biomedical Materials Research, 27, 1553- 1557, "Fibroblast Anchorage to Microtextured Surfaces" (1993). Zibaitis et al., "Cellular Cardiomyoplasty: Biological Basis, Current Hypothesis and Future Perspective", Cellular Cardiomyoplasty: Myocardiol Repair with Cell Implantation, eds. R. Kao and R. C-J. Chiu, Landes Bioscience (1997). ______________________________________
All patent and nonpatent documents listed in Table 1 are hereby incorporated by reference herein in their respective entireties. As those of ordinary skill in the art will appreciate upon reading the Summary of the Invention, Detailed Description of Preferred Embodiments, and Claims set forth below, many of the systems, devices, and methods disclosed in these documents may be modified advantageously by using the teachings of the present invention.